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Nijhuis et al. Orphanet J Rare Dis (2021) 16:140 https://doi.org/10.1186/s13023-021-01682-y
RESEARCH
A standard set of outcome measures for the comprehensive assessment of osteogenesis imperfectaWouter Nijhuis1* , Anton Franken2, Kara Ayers3, Chantal Damas4, Lars Folkestad5, Antonella Forlino6, Paolo Fraschini7, Claire Hill8, Guus Janus2, Richard Kruse9, Lena Lande Wekre10, Lieve Michiels11, Kathleen Montpetit12, Leonardo Panzeri13, Valerie Porquet‑Bordes14, Frank Rauch4, Ralph Sakkers1, Jean‑Pierre Salles14, Oliver Semler15, Jony Sun16, Michael To17, Laura Tosi18, Yangyang Yao19, Eric Hiu Kwong Yeung17, Lidiia Zhytnik20, Maria Carola Zillikens21 and Marjolein Verhoef1
Abstract
Background: Osteogenesis Imperfecta (OI) is a genetic disorder also known as ‘brittle bone disease’. The clinical manifestation of OI shows a wide variation. Therefore, care for patients with OI requires an interdisciplinary approach. The effectiveness of particular interventions and treatment protocols of interdisciplinary teams is not clear due to a non‑standardized and wide variation of patient outcomes thus making the comparison of outcome measures avail‑able in the literature difficult. It is only by agreeing on a common, standard set of outcome measures for the compre‑hensive appraisal of OI that comparisons across interdisciplinary treatment centers for OI will be possible in the future.
Methods: The Key4OI international interdisciplinary working group of 27 members used a consensus‑driven modi‑fied Delphi approach to develop a set of global outcome measures for patients with OI. The International Classifica‑tion of Functioning, Disability and Health (ICF), was used to define domains and organize the outcomes from the literature search. After reviewing the outcomes extracted from the literature, trials and registries, the working group agreed on a final selection of domains and their definition (ICF definition as well as a lay description). These domains were then presented to the focus groups who prioritized the outcome domains by taking into account the items important to the OI community. All content was collected and analyzed and final domains were determined. A con‑sensus of appropriate measuring instruments for each domain was reached with Delphi rounds. The entire approach was in line with the International Consortium for Health Outcomes Measurement ICHOM methodology.
Results: More than 400 different outcome measures were identified in our literature search. After three Delphi rounds, 24 domains were selected. After the focus group sessions, the number of domains were reduced to 15. A consensus was reached on the measuring instruments to cover these domains for both children and adults.
Conclusion: The Key4OI project resulted in standard set of outcome measures focused on the needs and wishes of individuals with OI and their families. This outcome set will enable healthcare teams and systems to compare and to improve their care pathways and quality of care worldwide. Further studies are needed to evaluate the implementa‑tion of this standardized outcome set.
© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Open Access
*Correspondence: W.H.Nijhuis‑2@umcutrecht.nl1 University Medical Center Utrecht, Utrecht, The NetherlandsFull list of author information is available at the end of the articleCoordinator: Dagmar Mekking, CEO Care4BrittleBones Foundation
Page 2 of 16Nijhuis et al. Orphanet J Rare Dis (2021) 16:140
BackgroundIn evidence-based health care, a key determining factor for research and evaluation of clinical care is the choice of outcomes. Outcome measuring instruments must be reliable, valid, and feasible [1,2]. Trials using inappro-priate instruments may overestimate, underestimate, or overlook the effect of an intervention [3]. Standardiza-tion is necessary in order to allow cross-trial compari-son in systematic reviews. Similarly, meta-analyses, needed for evidence-based clinical practice guidelines, are only possible with validated and comparable out-comes [4]. Osteogenesis Imperfecta (OI) is a genetic disorder also known as ‘brittle bone disease’ Autoso-mal dominant mutations in the type I collagen cod-ing genes (COL1A1 and COL1A2) affect the collagen structure in the majority of OI patients. More recently recessive, dominant and X-linked defects in a wide variety of genes encoding proteins involved in type I collagen synthesis have been shown to cause osteo-genesis imperfecta [5]. The current non-standardized and wide variation of outcomes in studies on patients with OI makes comparison of data difficult. Many stud-ies and registries on OI exhibit marked heterogeneity in terms of what domains are measured and how the domains are defined. Outcome research in OI is espe-cially difficult because of the inherent complexity of the condition. OI does not only affect bone but all tissues containing collagen type I as well. The clinical manifes-tations vary widely between the different types of OI ranging from patients who have mild symptoms with a normal life expectancy to intrauterine death [6–8]. Even within the same type of OI there is a wide spec-trum of clinical manifestations.
From birth to young adulthood, a child grows and develops in all domains such as mobility, self-care and participation. In addition, there is development toward independence and maturity. For all these stages, with their own particular focus and perspective, outcomes that are comparable worldwide, are important for fur-ther improvement of high-quality interdisciplinary care [9].
The challenge will be to define a set of outcomes for patients with OI that covers all the important domains, especially since the relevant outcome data will be differ-ent for different ages. To meet this challenge, the Care-4BrittleBones foundation initiated Key4OI, a project to develop a minimum standard set of outcomes and asso-ciated measures for the comprehensive appraisal of OI
that would reflect the complexity of interdisciplinary OI care and focus on what matters most to patients with OI and their families.
ObjectivesThe primary objective of this initiative was to reach an international, interdisciplinary consensus for a standard set of outcomes and associated measuring instruments for the care of individuals with OI, based on what is important to both experts and patients. This standard set would be comprehensive enough to cover the full range of OI care, yet practical enough for sustainable imple-mentation. This will permit teams around the world to measure their performance in a consistent way. This will support longitudinal and cross-sectional comparison of outcomes between centers that serve OI—populations in different environments.
MethodsA modified Delphi technique was used to develop a mini-mal standard outcome set. The Delphi technique is an iterative multi stage process to actively transform opinion into group consensus [10, 11].
This consensus must be based on data derived from all stakeholders involved in the care of individuals with OI including the people with OI themselves. In order to achieve this, an assembly of three groups from the OI community was formed, consisting of a lead team, an expert team and focus groups. In each country an ethical review was conducted and ethical approval was obtained where required.
The lead team consisted of six professionals, five were members of a pediatric or adult OI interdisciplinary team and the sixth was the coordinator from the non-govern-ment organization (NGO) Care4BrittleBones. The role of the lead team was to drive the overall project, spear-head the initial research and literature search, and pre-pare all materials for the video conferences, expert team meetings and focus groups. The expert team consisted of 21 professionals. Membership included internation-ally recognized professionals, as well as representatives of patient organizations from different countries. Over-all, eight countries on three continents were represented. Clinical disciplines represented included orthopedic surgery, rehabilitation, genetics, pediatrics, psychology, physiotherapy, occupational therapy and endocrinology. The background of the professionals who participated is shown in Table 1. The role of the expert team was to
Keywords: Osteogenesis imperfecta, Brittle bone disease, Continuous quality improvement, Learning health care, Outcomes, Patient‑reported outcomes measures, Value‑based health care, Clinical outcome measures
Page 3 of 16Nijhuis et al. Orphanet J Rare Dis (2021) 16:140
Tabl
e 1
Det
ails
of e
xper
t tea
m m
embe
rs
Role
Nam
eSu
rnam
eTi
tleLo
catio
nPr
of. b
ackg
roun
dA
dditi
onal
pe
rspe
ctiv
eEm
aila
dres
sIn
stitu
te
Lead
Tea
mA
nton
FRA
NKE
NFr
anke
nM
D, P
hDZw
olle
, the
Net
her‑
land
sEn
docr
inol
ogis
ta.
a.m
.fran
ken@
isal
a.nl
Isal
a H
ospi
tal
Lead
Tea
mG
uus
JAN
US
Janu
sM
D, P
hDZw
olle
, the
Net
her‑
land
sO
rtho
paed
ic S
ur‑
geon
a.j.m
.janu
s@is
ala.
nlIs
ala
Hos
pita
l
Lead
Tea
mW
oute
r NIJH
UIS
Nijh
uis
MD
Utr
echt
, the
Net
her‑
land
sO
rtho
paed
ic S
ur‑
geon
W.H
.Nijh
uis‑
2@um
cutr
echt
.nl
Uni
vers
ity M
edic
al
Cent
er U
trec
ht
Lead
Tea
mRa
lph
SAKK
ERS
Sakk
ers
MD
, PhD
Utr
echt
, the
Net
her‑
land
sO
rtho
paed
ic S
ur‑
geon
OIF
E M
edic
al A
dvi‑
sory
Boa
rd M
embe
rR.
Sakk
ers@
umcu
tre‑
cht.n
lU
nive
rsity
Med
ical
Ce
nter
Utr
echt
Lead
Tea
mM
arjo
lein
VER
HO
EFVe
rhoe
fM
D, P
hDU
trec
ht, t
he N
ethe
r‑la
nds
Reha
bilit
atio
n Ph
ysi‑
cian
M.V
erho
ef‑1
9@um
cutr
echt
.nl
Uni
vers
ity M
edic
al
Cent
er U
trec
ht
Lead
Tea
m (P
roje
ct
Mgt
)D
agm
ar M
EKKI
NG
Mek
king
PhD
The
Hag
ue, t
he
Net
herla
nds
Proj
ect M
anag
erD
irect
or C
are4
Britt
le‑
Bone
s Fo
unda
tion,
O
I‑com
mun
ity
dagm
ar.m
ekki
ng@
care
4brit
tlebo
nes.
org
Care
4Brit
tleBo
nes
Foun
datio
n
Expe
rt T
eam
Kara
AYE
RSA
yers
PhD
Cin
cinn
ati,
USA
Psyc
holo
gist
Vice
‑Pre
side
nt O
IF
Boar
d of
Dire
ctor
s, O
I‑com
mun
ity
Kara
.Aye
rs@
cchm
c.or
gC
inci
nnat
i Chi
ldre
n’s
Hos
pita
l Med
ical
Ce
nter
Expe
rt T
eam
Cha
ntal
DA
MA
SD
amas
BSc
Mon
trea
l, Ca
nada
Phys
ioth
erap
ist
Coor
dina
tor C
ente
r of
Exc
elle
nce
CD
amas
@sh
rinen
et.
org
Shrin
ers
Hos
pita
ls fo
r C
hild
ren,
Mon
trea
l
Expe
rt T
eam
Lars
FO
LKES
TAD
Folk
esta
dM
D, P
hDO
dens
e, D
enm
ark
Endo
crin
olog
ist
OIF
E M
edic
al
Adv
isor
y Bo
ard
Mem
ber,
Care
4Brit
‑tle
Bone
s Fo
unda
‑tio
n A
dvis
ory
Boar
d M
embe
r
lfolk
esta
d@he
alth
.sd
u.dk
Uni
vers
ity o
f Sou
ther
n D
enm
ark
Expe
rt T
eam
Ant
onel
la F
ORL
INO
Forli
noPh
DPa
via,
Ital
yBi
oche
mis
try,
Gen
et‑
ics
OIF
E M
edic
al
Adv
isor
y Bo
ard
Mem
ber,
Care
4Brit
‑tle
Bone
s Fo
unda
‑tio
n A
dvis
ory
Boar
d M
embe
r
anto
nella
.forli
no@
unip
v.it
Uni
vers
ity o
f Pav
ia
Expe
rt T
eam
Paol
o FR
ASC
HIN
IFr
asch
ini
MD
Mila
no, I
taly
Reha
bilit
atio
n Ph
ysi‑
cian
paol
ofra
schi
ni@
gmai
l.com
Rizz
oli I
nstit
ute
Bolo
‑gn
a Ve
le a
fflia
ties
Expe
rt T
eam
Cla
ire H
ILL
Hill
PhD
, MC
SP P
GC
ESh
effiel
d, U
KPh
ysio
ther
apis
tO
IFE
Med
ical
Adv
i‑so
ry B
oard
Mem
ber
clai
rehi
ll321
6@gm
ail.
com
Sheffi
elds
Chi
ldre
n’s
NH
S tr
ust f
ound
atio
n
Expe
rt T
eam
Rich
ard
KRU
SEKr
use
DO
, MBA
Del
awar
e, U
SAO
rtho
paed
ic S
ur‑
geon
Rich
ard.
Krus
e@ne
mou
rs.o
rgN
emou
rs/A
lfred
D
upon
t Hos
pita
l for
ch
ildre
n
Page 4 of 16Nijhuis et al. Orphanet J Rare Dis (2021) 16:140
Tabl
e 1
(con
tinue
d)
Role
Nam
eSu
rnam
eTi
tleLo
catio
nPr
of. b
ackg
roun
dA
dditi
onal
pe
rspe
ctiv
eEm
aila
dres
sIn
stitu
te
Expe
rt T
eam
Lena
LA
ND
E W
EKRE
Wek
reM
D, P
hDO
slo,
Nor
way
Reha
bilit
atio
n Ph
ysi‑
cian
OIF
E M
edic
al
Adv
isor
y Bo
ard
Mem
ber,
Care
4Brit
‑tle
Bone
s Fo
unda
‑tio
n A
dvis
ory
Boar
d M
embe
r
LEN
ALW
@su
nnaa
s.no
TRS
Nat
iona
l Res
ourc
e Ce
nter
for R
are
Dis
orde
rs, S
un‑
naas
Reh
abili
tatio
n H
ospi
tal
Expe
rt T
eam
Liev
e M
ICH
IELS
Mic
hiel
sPh
DBe
lgiu
mno
t app
licab
leBo
ard
mem
ber Z
OI,
Belg
ium
OI A
ssoc
ia‑
tion,
OI C
omm
unity
dille
n.m
ichi
els@
skyn
et.b
eZO
I (Fl
emis
h O
I Ass
o‑ci
atio
n)
Expe
rt T
eam
Kath
leen
MO
NTP
ETIT
Mon
tpet
itM
ScO
TM
ontr
eal,
Cana
daO
ccup
atio
nal T
hera
‑pi
st, r
etire
dA
dvis
or C
are4
Britt
le‑
Bone
s Fo
unda
tion
kath
leen
mon
tpet
it@ya
hoo.
caCa
re4B
rittle
Bone
s Fo
unda
tion
Expe
rt T
eam
Leon
ardo
PA
NZE
RIPa
nzer
ino
t app
licab
leIta
lyno
t app
licab
lePr
esid
ent I
talia
n O
I Ass
ocia
tion
AS.
IT.O
.I., O
I Com
‑m
unity
leon
ardo
.pan
zeri@
asito
i.it
AS.
IT.O
.I. (It
alia
n O
I A
ssoc
iatio
n)
Expe
rt T
eam
Vale
rie P
ORQ
UET
‑BO
RDES
Bord
esM
D, P
hDTo
ulou
se, F
ranc
ePe
diat
ricia
nCa
re4B
rittle
Bone
s Fo
unda
tion
Adv
i‑so
ry B
oard
Mem
ber
porq
uet‑
bord
es.v
@ch
u‑to
ulou
se.fr
CH
U d
e To
ulou
se
Expe
rt T
eam
Fran
k RA
UC
HRa
uch
MD
, PhD
Mon
trea
l, Ca
nada
Pedi
atric
ian
frank
.rauc
h@m
cgill
.ca
Shrin
ers
Hos
pita
ls fo
r C
hild
ren,
Mon
trea
l
Expe
rt T
eam
Jean
‑Pie
rre
SALL
ESSa
lles
MD
, PhD
Toul
ouse
, Fra
nce
Phys
iopa
thol
ogis
tsa
lles.j
p@ch
u‑to
u‑lo
use.
frC
HU
de
Toul
ouse
Expe
rt T
eam
Oliv
er S
EMLE
RSe
mle
rM
DCo
logn
e, G
erm
any
Pedi
atric
ian
OIF
E M
edic
al
Adv
isor
y Bo
ard
Mem
ber,
Care
4Brit
‑tle
Bone
s Fo
unda
‑tio
n A
dvis
ory
Boar
d M
embe
r, O
I‑com
mun
ity
joer
g.se
mle
r@uk
‑ko
eln.
deU
nive
rsity
of C
olog
ne,
Dep
artm
ent o
f Pa
edia
tric
s
Expe
rt T
eam
Jony
SU
NSu
nM
SW, P
roje
ct M
an‑
ager
Beiji
ng, C
hina
Soci
al W
orke
rC
hina
‑Dol
ls C
ente
r fo
r Rar
e D
isor
ders
(C
CRD
), O
I Com
‑m
unity
82,4
56,2
14@
qq.c
omC
hina
‑Dol
ls C
ente
r for
Ra
re D
isor
ders
(CC
RD)
Expe
rt T
eam
Mic
hael
TO
ToM
D, P
hDH
ong
Kong
SA
R an
d Sh
enzh
en, C
hina
Ort
hopa
edic
Sur
‑ge
onm
ikek
tto@
hku.
hkTh
e U
nive
rsity
of H
ong
Kong
—Sh
enzh
en
Hos
pita
l
Expe
rt T
eam
Laur
a TO
SITo
siM
DW
ashi
ngto
n, U
SAO
rtho
paed
ic S
ur‑
geon
OIF
Med
ical
Adv
iory
Bo
ard
LTO
SI@
child
rens
na‑
tiona
l.org
Chi
ldre
n’s
Nat
iona
l H
ospi
tal, W
ashi
ng‑
ton,
DC
Expe
rt T
eam
Yang
yang
YA
OYa
oM
DSh
ando
ng P
rovi
ncia
l H
ospi
tal,
Chi
naO
rtho
paed
ic S
ur‑
geon
15,1
65,3
13,3
44@
126.
com
Shan
dong
Pro
vinc
ial
Hos
pita
l
Page 5 of 16Nijhuis et al. Orphanet J Rare Dis (2021) 16:140
Tabl
e 1
(con
tinue
d)
Role
Nam
eSu
rnam
eTi
tleLo
catio
nPr
of. b
ackg
roun
dA
dditi
onal
pe
rspe
ctiv
eEm
aila
dres
sIn
stitu
te
Expe
rt T
eam
Eric
Hiu
Kw
ong
YEU
NG
Yeun
gM
Sc, B
ScH
ong
Kong
SA
R an
d Sh
enzh
en, C
hina
Phys
ioth
erap
ist
eric
yhk@
hku.
hkTh
e U
nive
rsity
of H
ong
Kong
—Sh
enzh
en
Hos
pita
l
Expe
rt T
eam
Lidi
ia Z
HYT
NIK
Zhyt
nik
PhD
Tart
u, E
ston
iaG
enet
ics,
Biom
edi‑
cine
OIF
E M
edic
al
Adv
isor
y Bo
ard
Mem
ber,
Care
4Brit
‑tle
Bone
s Fo
unda
‑tio
n A
dvis
ory
Boar
d M
embe
r, O
I‑com
mun
ity
Lidi
ia.z
hytn
ik@
ut.e
eTa
rtu
Uni
vers
ity
Hos
pita
l
Expe
rt T
eam
Mar
ia C
arol
a ZI
L‑LI
KEN
SZi
llike
nsPr
of. M
D, P
hD,
Rott
erda
m, t
he N
eth‑
erla
nds
Endo
crin
olog
ist
m.c
.zill
iken
s@er
as‑
mus
mc.
nlU
nive
rsity
Med
ical
Ce
nter
Era
smus
Rot
‑te
rdam
Page 6 of 16Nijhuis et al. Orphanet J Rare Dis (2021) 16:140
advise and provide input on materials presented by the lead team, engage with others and work towards consen-sus by participating in Delphi rounds.
Focus groups of either adults or children (ages 10–18 years) were held in 11 different countries over 3 continents to determine which domains matter most to the OI community worldwide and were set up with the help of local OI patient organizations. The people with OI described the level of severity of their condition (mild, moderate or severe) as well as their ambulatory status. No medical confirmation was asked. We did not record the type of OI. All focus groups consisted of a range of severity and when possible, each country held an adult as well as a child focus group. The minimum number of participants in a focus group was five for children and eight for adults. Only individuals with OI themselves were included and not their parents. Literature on focus groups advises clustering children and youth per age group, allowing a discussion among peers. Teens show an increased ability in abstract reasoning, problem solving and decision making [12].Thus focus groups were with children from 10 to 18 years old. In addition we asked the adults to reflect on their youth in order to gain further information about the younger age groups.
In order to reach consensus on every decision, modi-fied Delphi rounds were held with the expert team. The lead team had no vote in the Delphi rounds. Over a period of one and a half years, the lead team together with the expert team held a total of 20 videoconferences. Also a final face to face meeting took place during an international conference in November 2019. Each meet-ing had at least 80% participation.
ProcessThe lead team conducted a literature search to identify all outcome domains reported in the medical literature. Broad search terms were used in order not to overlook any domains. The search terms were Brittle Bone Dis-ease and Osteogenesis Imperfecta. Inclusion criteria were original research articles, publications issued in the past five years, registries, multicenter studies, clini-cal trials and publications in peer-reviewed journals. Exclusion criteria were articles not available in English, the inability to obtain the full-text article, abstracts, edi-torials, commentaries, letters, and case reports. All out-comes reported in the included articles together with the outcomes collected in three ongoing unpublished trials (TOPAZ, BOOSTB4 and Mereo) and four known regis-tries (UMC Utrecht, Isala, USA linked clinical research and Cologne) were collected into one database.
Next step was the aggregation of the data follow-ing the structure of the International Classification of Functioning, Disability and Health (ICF). The ICF is an
international classification that describes a health con-dition in terms of body functions and structure, activi-ties and participation and personal and environmental factors as well as how they are interrelated [13]. All 191 WHO Member States officially endorsed the ICF in 2001 as the international standard to describe and measure health and disability (Fig. 1).
After reviewing the outcomes extracted from the lit-erature, trials and registries, the lead team identified domains and the expert team proceeded to prioritize these domains. After three modified Delphi rounds, the expert team agreed on a final selection of these domains and their definition (ICF definition as well as a lay description). These domains were then presented to the focus groups after translation into the languages appro-priate for the countries in which the focus groups were held.
The process for the focus groups was described in a detailed protocol including a standard set of slides and a scoring sheet to identify and prioritize the outcome domains taking into account the items of importance for the OI community and their wishes and hopes for the future per domain. Domains were ranked and then added or removed as per group consensus. The standardized approach was discussed at the outset with the national OI patient organizations in each country in order to respect the cultural aspects and to ensure that in each cultural setting the participants would feel comfortable to speak up in order to obtain outcomes of consistent quality. All content was collected and analyzed by the lead team and the final domains were determined by the expert team. Ethical review for the focus groups was obtained accord-ing to local requirements.
The subsequent step was the selection of the appro-priate measuring instruments for each domain by the lead team, using a database and library of measuring instruments based on the literature and clinical prac-tice. Guided by the feedback from the focus groups, sustainability and validity of the measures per domain, a pre-selection was made. Practical issues such as time required, resources needed and availability of the instru-ment were taken into account. A generic measuring instrument was preferred over a disease specific instru-ment to enable generic disease comparison in the future. A single instrument covering multiple domains with dif-ferent subscales was preferred over using multiple instru-ments. This pre-selection was evaluated by the expert team who added additional measuring instruments and personal feedback on the selection and use of the meas-uring instruments from their own clinical practice. In a next Delphi round, experts were asked to rate the instruments on a 9-point scale. A minimum percentage of 80% with a score 7, 8 or 9 was required for the final
Page 7 of 16Nijhuis et al. Orphanet J Rare Dis (2021) 16:140
confirmation of a measuring instrument. A score of 1, 2 and 3 in 80% of the responses lead to a final rejection of the measurement instrument. Mid-range scores were considered “non-conclusive”, discussed in the next expert meeting, and tabled in the next Delphi round. A partici-pation rate of 80% of experts was required in the Delphi rounds. The entire approach was in line with the Inter-national Consortium for Health Outcomes Measurement ICHOM methodology [14].
ResultsSelection of outcome domainsThe literature search yielded over 6000 hits including 19 trials, 16 multicenter studies, and 2 registry studies. After correction for duplicates, 49 articles were reviewed and resulted in a database of 402 different outcome domains. After reducing the 402 domains reported in the literature to 44, these domains were then prioritized by the expert team through 3 modified Delphi rounds and 24 domains were selected (Table 2). These 24 domains with the ICF definition as well as a lay description were then presented to the focus groups. An overview of the process of select-ing the outcome domains and measurements can be found in the flowchart in Fig. 2.
The focus groups for children had 41 participants with a mean age of 14, 1 (STDEV 2.32) (10–18 years of age) of whom 66% was female. Mobility level of the partici-pants was 46% ambulant, 49% wheelchair and 5% both wheelchair and ambulant. The adult focus groups had 71 participants with a mean age of 33.7 (STDEV 12.3) 16–70 years of age. 63% of the adults were female. Mobil-ity level was 28% ambulant, 49% wheelchair and 23% both wheelchair and ambulant. All focus groups had a mixture of different OI types. Focus groups were held in Belgium, Canada, Chile, China/Hong Kong, France, Germany,
Italy, the Netherlands, Russia, UK and USA. The cumu-lative time of discussion in these groups was 80 h.
The focus group resulted in a prioritized list of domains. In addition, 23 new issues appeared. For exam-ple, in the domain ‘pain’ often "the inability to work" was suggested. After discussion by the expert group the majority of the issues appeared to be covered by the domains initially selected and all issues were felt to be part of one of the 24 designated domains or part of the demographic profile (Table 3). Based on the priorities indicated by the focus groups as well as the overall eval-uation of the expert team, the final number of domains was reduced to 15 for children and 13 for adults with OI (Table 2). All domains were structured according to the WHO ICF [13] and categorized within 4 major themes; major events, clinical status, functioning and quality of life (Table 3).
Selection of outcome measuring instrumentsAfter four Delphi rounds the expert team reached con-sensus on the final set of measuring instruments shown in Table 3. For most domains, agreement was reached within the 1st and 2nd Delphi rounds. Some domains needed more discussion particularly those covered by patient reported outcomes measures (PROMs) covering multiple domains.
In these cases, the domains were discussed in combina-tion because it was preferable to opt for one instrument that covered multiple domains with different subscales over different single domain instruments.
The PROMs that needed further discussion for chil-dren were Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Instrument banks (Ped), the Pediatric Quality of Life Inventory (Ped-sQL) and the Pediatric Outcomes Data Collection Instru-ment (PODCI), which each cover several domains (pain interference, lower limb function, upper limb function, fatigue, emotional wellbeing, social functioning, self-care and participation) [15, 16]. Regarding Clinical Outcome Measures (COMs), the Functional Mobility Scale (FMS), the Gillette Functional Assessment Questionnaire (FAQ), 30 s walk test and the Medical Research Counsel (MRC) scales for manual muscle testing were discussed. The measuring instruments were again introduced in the 3rd and 4th Delphi round. Despite the PedsQL being conclu-sive for social functioning in the first Delphi round, the final Delphi round resulted in agreement on the use of the PROMIS Ped scales for all domains and consensus was reached for 28 measures (Table 3).
In contrast to the many options discussed for chil-dren with OI, the discussion in relation to adult care was more focused. Of the 19 pre-selected instruments, 8 were agreed on after the first Delphi round. With the second
Fig. 1 Model of the international classification of functioning, disability and health (ICF). The ICF conceptualizes a person’s level of functioning as a dynamic interaction between her or his health conditions, environmental factors, and personal factors [13]
Page 8 of 16Nijhuis et al. Orphanet J Rare Dis (2021) 16:140
Delphi round, unanimous agreement was reached on 18 instruments. PROMIS was preferred over the Short Form (36) Health Survey (SF-36), due to the latter’s poor sensitivity in screening for the psychosocial issues and the time required resulting in a negative impact on the completion rates [17]. The possibility for computer adap-tive testing (CAT) by PROMIS was seen as a significant advantage over SF-36. For the sake of using one instru-ment rather than two, PROMIS will also be used for the fatigue measurements. In a third Delphi round, consen-sus was reached on the final set of 24 outcome measures covering all domains (Table 3).
Considerations per theme and domainMajor eventsFracturesThe expert team and focus groups expressed the need to address all aspects of bone fractures. Incidence, heal-ing and type of treatment, as well as the mechanism of fracture (low impact vs high impact) in children will be reported. Incidence will be reported as the sum of clini-cally reported fractures, patient reported fractures and radiologically confirmed fractures, considering that not all fractures are always clearly visible on radiologic imag-ing. In daily practice, many patients are treated for clini-cal fractures without radiologic imaging or will manage minor fractures themselves without hospital visits and minimize the exposure to radiation.
SurgeryThe focus groups defined surgeries as major life events in the majority of cases, as the severity of the disease and the quality of healthcare was determined by the
complexity and frequency of surgery and the outcome. The expert team decided to record these events.
Clinical statusBone mineral density (BMD)BMD, measured with Dual-Energy X-ray Absorptiometry scan (DXA-scan), is currently widely used as a substitute parameter for bone quality in OI and monitoring of med-ical treatment. Therefore a DXA-scan was selected as the preferred outcome measurement, despite its shortcom-ings of not taking into account altered body shape and the lack of a linear correlation to the fragility of the bones [18].
Spinal deformityThe expert team agreed to include the measurement of scoliosis and kyphosis with Cobb angles on total spine X-rays as spinal deformities are common in OI and severe malformations of the spine may lead to various other problems affecting quality of life.
JointsThe Beighton Score was selected to measure joint laxity during growth [19]. As laxity does not change in adult-hood the Beighton Score will only be measured once at baseline.
Limb anomaliesGiven the frequency of malalignment, the relation between bowing and fractures, the possibility for guided growth, and the need for surgery to improve function if significant malalignment is present, the expert team
Table 2 Selected domainsADULTS CHILDREN & ADOLESCENTS
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16Total Rank
area The Netherlands adults
Russia adults
Germany adults
Italy adults
Belgium adults
Chile adults
France adults
China adults
USA adults (virtual)
The Netherlands children
Russia children
Italy children
UK children
France children
Canada - children
China children
ALL Adults only
1 Fractures 16 24 23 21 23 19 18 22 23 24 24 24 24 18 20 24 347 1892 Pain 24 22 12 13 24 23 23 21 22 22 23 19 21 22 24 22 315 1843 Spine 10 23 15 22 21 22 21 19 15 18 20 23 18 24 13 10 284 1684 Bone mineral density 15 21 20 19 19 21 16 14 13 17 21 22 8 21 22 21 269 1585 Lower limb function 21 19 22 16 22 15 20 18 5 11 22 21 10 23 18 20 263 1586 Emotional wellbeing 23 12 16 11 20 14 11 4 19 10 15 20 19 19 21 13 234 1307 Fatigue 22 13 10 8 10 16 24 6 24 12 16 11 23 16 23 6 234 1338 Limb anomalies 18 20 9 17 16 17 15 24 6 23 18 15 14 12 8 15 232 1429 Teeth 3 17 6 23 6 24 22 17 14 20 10 13 16 20 14 18 225 132
10 Joints 19 15 7 15 18 18 14 15 16 21 13 17 12 10 6 14 216 13711 Short stature / growth 6 18 11 24 17 7 4 20 2 15 19 5 22 14 10 19 194 10912 Surgery 13 16 19 20 9 13 9 7 9 14 17 4 7 17 17 17 191 11513 Fracture healing 4 14 18 18 1 11 7 11 18 19 14 12 15 3 19 9 184 10214 Upper limb function 20 11 3 12 15 20 12 13 1 16 8 6 17 13 9 7 176 10715 Social functioning 17 8 21 10 14 4 3 3 10 9 11 16 9 15 16 11 166 9016 Schooling/education or 14 1 13 6 5 3 5 23 11 13 5 18 11 2 7 23 137 8117 Respiratory function 7 10 2 14 2 10 6 9 21 5 12 7 13 9 4 1 131 8118 Domestic life 8 2 17 9 12 8 17 2 7 4 9 3 5 11 12 16 126 8219 Changing / maintaining body 11 5 5 5 11 6 13 10 8 6 7 10 4 7 15 8 123 7420 Recreation and leisure 5 3 14 3 8 2 1 16 3 8 1 14 20 6 11 4 115 5521 Reproductive system 12 6 24 2 7 1 18 12 12 7 3 2 1 4 2 2 113 9422 Hearing 9 9 1 7 13 9 10 5 17 2 2 8 6 8 3 3 109 8023 Personal self-care 2 4 8 4 3 5 8 1 4 3 6 9 3 5 5 12 70 3924 Cardiovascular function 1 7 4 1 4 12 2 8 20 1 4 1 2 1 1 5 69 59
OVERALL RESULTSChildren & adolescents only
158131116111105104101
9093798576826976565044496019293110
The results of ranking by all the focus groups. The darker the background the higher the rating of the domain. The bolded domains are the final selected domains based on the priorities indicated by the focus groups as well as the overal evaluation of the expert team. The domains recreation and leisure were combined in to one domain called participation
Page 9 of 16Nijhuis et al. Orphanet J Rare Dis (2021) 16:140
chose long standing axis X-rays to measure and report on limb alignment.
Short stature and growthPhysical appearance was considered an important issue during the focus group sessions, however no clinician or patient reported rating was found. Growth and stature by measuring height was determined to be the best way to express and monitor this domain.
FunctionUpper limb functionFor the measurement of upper limb function and its impact on independence in daily life, the PROMIS Ped—upper extremity and PROMIS—upper extremity for adults were selected for children and adults [15]. Other PROMs and other COMs were felt to be too extensive for screening (e.g. ABILHAND-Kids, Bayley Scales of Infant Development, Peabody Developmen-tal Motor Scales) or were not applicable to the majority of people with OI (e.g. the Brief Assessment of Motor Function (BAMF)).
Lower limb functionMeasurement instruments from the literature search as well as those instruments suggested by the experts resulted in a choice of more than 30 instruments. There was consensus on using a combination of PROMs and COMs to describe clinical assessment as well as “real life” performance. Whilst feedback on the PROMIS Ped—mobility module to measure lower limb function was conclusive in the 2nd Delphi round, the choice of COM was not. The Gillette FAQ, BAMF, FMS, the timed up and go test and the 6 min, 1 min and 30 s walking tests were all discussed as possible options. The 30 s walking test was selected by the experts for both children and adults. It is the least burdensome, allows some measure-ment of progression and gives an outcome when walking is present [20]. For classifying functional mobility, the FMS was chosen for children, as it records the range of assistive devices a child may use and therefore provides information on the different assistive devices used in dif-ferent environments [21].
For adults there was a good level of support among the experts for the PROMIS—physical functioning module as the PROM and the 30 s walking test as the COM.
Self‑careAge is a determining factor in this domain as adults have different goals in self-care compared to young children. For children the Functional Independence Measure for children (WeeFIM), PODCI, PedsQL, and
PROMIS were discussed. As a relatively small percent-age of children with OI have issues with self-care, (often due to upper extremity issues) the expert team con-cluded that screening for self-care problems in children could be addressed in the core set of measurements. Therefore, the expert team chose the PROMIS—upper limb module as screening instrument instead of the more detailed but time-consuming WeeFIM tool. If indicated, more specific instruments tailored to meas-ure self-care skills are available.
In adults, the SF-36, PROMIS—upper extremity module and the Sunnaas index of ADL (SI)
were considered. The expert team felt that a more extensive self-care assessment was warranted for adults. As such, the SI was chosen over the SF-36 (with only one item on self-care) to complement the PROMIS—upper extremity module [15, 22].
Quality of lifePainThe focus groups reported pain as an important issue for individuals with OI as it affects daily life, mobility, par-ticipation, work life and social relationships. Pain was subdivided by the focus groups into acute pain such as in the case of fractures and chronic/persevering pain. Based on the strong support for PROMIS modules overall and no clear preference between PROMIS Ped—pain inter-ference, PODCI and PedsQL, the expert team chose the PROMIS Ped—pain interference for children in the final outcome set. For pain intensity in children, the colored visual analog pain scale [23] was selected. In adults, both PROMIS—pain interference and pain intensity subscales were selected after the first 2 Delphi rounds.
FatigueThe adult focus groups indicated fatigue was a notable problem, and it was also referenced in the child focus groups. For children, PROMIS Ped—fatigue as meas-urement tool was strongly preferred over PedsQL and PODCI.
For adults, the SF-36 vitality scale and PROMIS—fatigue remained after 2 Delphi rounds. Finally, the PROMIS—fatigue was chosen based on the strong sup-port for the PROMIS modules overall [15].
Emotional well‑beingPsychosocial issues are more prominent in OI compared to other disabilities [24]. Emotional well-being is a broad concept, which needed to be specified for the OI popula-tion. The expert team as well as the focus groups agreed on the importance of anxiety and mood. PROMIS Ped, PedsQL and PODCI contain some subscales covering emotional well-being. In the 2nd Delphi round there was
Page 10 of 16Nijhuis et al. Orphanet J Rare Dis (2021) 16:140
a slight preference for using the PROMIS Ped scales and in the fourth Delphi round there was full agreement on using the PROMIS Ped—emotional distress anxiety and depression subscale to cover emotional well-being.
For adults the 3rd Delphi round resulted in strong support for the PROMIS—anxiety and depression sub-scales. The SF-36 (Emotional role functioning and mental health), the WHO QOL-BREF as well as the HADS were also subject to discussion but garnered low support in the first and second Delphi round.
Social functioningAgain, the PROMS PedsQL, PODCI and PROMIS Ped were suggested as the best options for the screening of social functioning in children with OI. Despite the Ped-sQL already being conclusive for social functioning in the first Delphi round, the final Delphi round resulted in agreement on the use of PROMIS Ped scales for all domains with PROMIS Ped -peer relationships replacing the PedsQL for social functioning.
For adults the SF-36, WHO Quality of Life—BREF (WHO QOL-BREF) social relationships, Female Sexual
Functioning Index (FSFI), International Index of Erec-tile Function (IIEF), PROMIS—ability to participate, PROMIS—sexual function and satisfaction measures were all discussed. The PROMIS—ability to participate had strong support in the first Delphi round and the PROMIS—sexual function and satisfaction measures were added in the second Delphi round.
ParticipationThe focus groups as well as the expert group agreed that social functioning and participation are equally important and both items were retained. For children it was difficult to find an instrument for participation, which was not too time-consuming. While there was a preference to use the PROMIS Ped scales when possible, the school subscale of the PedsQL was optimal for participation and was selected [16]. Participation is also embedded in the PODCI but cannot be easily retrieved as a separate subscale.
For adults, participation is measured by the PROMIS—ability to participate in social roles and activities (already chosen to measure social functioning) as well as the PROMIS—satisfaction with social participation. Both had high support in the 2nd Delphi round. The SF-36 -Mental Health domain—social function, was found to be less suitable in the 2nd Delphi round.
DiscussionThe ICHOM methodology [14] was used to create a standardized set of outcomes based on the priorities of people with OI. An international group of health care providers, researchers and OI patient support organiza-tions produced a consensus on a standard set for use in OI clinics around the world. All disciplines involved in care for OI participated as well adults and children with different types of OI were represented in order to meas-ure what matters most to all people with OI. Individu-als with OI are a very heterogeneous group. Creating a subset of outcome measures according to type/severity would be challenging. For example, a person categorized as type I may have a phenotype quite similar to some-one identified as type IV. Creating subsets of outcome measures for each type or level of severity was consid-ered. However, the goal of this project was to develop a minimal set of outcomes measures encompassing the most important domains for the majority of individuals with OI regardless of type worldwide. This standard set can be used to measure, analyze and improve outcomes achieved in the delivery of care. We recognize this set will require continual review.
There were differences between countries in terms of ranking the domains and this may be explained in part by cultural differences. However, the twelve domains rated most important were ranked as such quite consistently
Fig. 2 Flowchart outcome domains and measurements
Page 11 of 16Nijhuis et al. Orphanet J Rare Dis (2021) 16:140
Tabl
e 3
Dem
ogra
phic
pro
file
and
outc
ome
them
es, f
our m
ajor
out
com
e th
emes
, dom
ains
and
sub
dom
ains
with
the
sele
cted
out
com
e m
easu
res
Patie
nt p
opul
atio
nM
easu
reSu
ppor
ting
info
rmat
ion
Tim
ing
Dat
a so
urce
Patie
nt d
emog
raph
ic fa
ctor
sD
iagn
osis
Clin
ical
All
patie
nts
Dat
e of
birt
hN
/A
Gen
der
Gen
der a
t birt
h
Patie
nt’s
stat
usPa
tient
aliv
e or
dea
d
If pr
evio
us q
uest
ion
is e
qual
to
“dea
th”:
Dat
e of
dea
thPa
tient
’s da
te o
f dea
th
Firs
t con
tact
with
spe
cial
ized
cen
ter
Dat
e of
the
first
con
tact
with
the
spec
ializ
ed c
ente
r
Age
at o
nset
Age
at w
hich
the
sym
ptom
s/si
gn fi
rst a
ppea
red
Age
at d
iagn
osis
Age
at w
hich
dia
gnos
is w
as m
ade
Fam
ily d
emog
raph
ic fa
ctor
s
All
patie
nts
Sibl
ing
with
OI
N/A
Fath
er w
ith O
IN
/A
Mot
her w
ith O
IN
/A
Base
line
clin
ical
stat
us
All
patie
nts
Dia
gnos
is O
IO
RPH
A c
ode
Dia
gnos
is O
IO
rpha
net c
ode
Gen
etic
sEx
act m
utat
ion
Inte
rnat
iona
l cla
ssifi
catio
n of
HG
VS (h
ttp:
// w
ww
. hgv
s. or
g)/H
GN
C/O
MIM
cod
e
Clin
ical
OI t
ype
Sille
nce
clas
sific
atio
n (T
ype
I–V
)
Patie
nt p
opul
atio
nM
easu
reM
easu
rem
ent t
ool
Tim
ing
(min
)D
ata
sour
ce
Maj
or e
vent
s
All
patie
nts
Frac
ture
sTh
e ap
prox
imat
e nu
mbe
r of h
isto
rical
frac
ture
sBa
selin
eSe
lf/pa
rent
repo
rted
All
patie
nts
Patie
nt re
port
ed fr
actu
re in
cide
nce
Chi
ldre
n: a
t dia
gnos
is a
nd 3
, 6, 8
, 11
, 15
year
s en
d of
pae
diat
ric
care
(< 1
8 ye
ars)
Adu
lts: 1
8 ye
ars
and
ever
y 5
year
s
Self/
pare
nt re
port
ed
All
patie
nts
Clin
ical
ly e
valu
ated
frac
ture
inci
denc
eC
linic
ala
All
patie
nts
X‑ra
y/ra
diol
ogic
ally
con
firm
ed fr
actu
re in
cide
nce
Chi
ldre
nM
echa
nism
(hig
h en
ergy
trau
ma,
low
ene
rgy
trau
ma,
unk
now
n)
All
patie
nts
Trea
tmen
t (su
rgic
al, c
onse
rvat
ive,
no
trea
tmen
t)
All
patie
nts
Frac
ture
hea
ling:
dur
atio
n <
2 m
onth
s, 2–
6 m
onth
s, >
6 m
onth
s, no
n‑un
ion
Chi
ldre
nSu
rger
yFr
eque
ncy
per y
ear
All
patie
nts
Type
of s
urge
ry
All
patie
nts
Reas
on: F
ract
ure/
defo
rmity
All
patie
nts
Frac
ture
hea
ling:
< 2
mon
ths,
2–6
mon
ths,
> 6
mon
ths,
non
unio
n
All
patie
nts
Reop
erat
ion
rate
Page 12 of 16Nijhuis et al. Orphanet J Rare Dis (2021) 16:140
Tabl
e 3
(con
tinue
d)
Patie
nt p
opul
atio
nM
easu
reM
easu
rem
ent t
ool
Tim
ing
(min
)D
ata
sour
ce
Clin
ical
sta
tus
All
patie
nts
Bone
min
eral
den
sity
DEX
A c
orre
cted
for h
eigh
tC
hild
ren:
yea
rlyC
linic
al
Adu
lts: 1
8 ye
ars
and
ever
y 5
year
s
Med
ical
trea
tmen
tC
hild
ren:
yea
rly
Adu
lts: 1
8 ye
ars
and
ever
y 5
year
s
Chi
ldre
nSp
ine
defo
rmity
X‑Ra
y To
tal S
pine
AP
and
Late
ral,
Cobb
ang
les
Chi
ldre
n: a
t dia
gnos
is a
nd 3
, 6, 8
, 11,
15
year
s en
d of
pae
diat
ric c
are
(< 1
8 ye
ars)
Adu
ltsA
dults
: bas
elin
e
Chi
ldre
nJo
ints
Beig
hton
(5 +
)C
hild
ren:
at d
iagn
osis
and
6, 8
, 11,
15
year
s en
d of
pae
diat
ric c
are
(< 1
8 ye
ars)
Adu
ltsA
dults
: bas
elin
e
Chi
ldre
nLi
mb
anom
alie
sLe
g le
ngth
dis
crep
ancy
: clin
ical
Chi
ldre
n: a
t dia
gnos
is a
nd 3
, 6, 8
, 11,
15
year
s en
d of
pae
diat
ric c
are
(< 1
8 ye
ars)
Chi
ldre
nLe
g le
ngth
dis
crep
ancy
: AP
and/
or la
tera
l St
andi
ng L
ong
Leg
X‑ra
ysC
hild
ren:
bas
elin
e at
8 y
ears
Adu
ltsLe
g le
ngth
dis
crep
ancy
: clin
ical
Adu
lts: b
asel
ine
Chi
ldre
nG
row
th a
nd w
eigh
tLe
ngth
(ove
rall
heig
ht)
Chi
ldre
n: y
early
Clin
ical
a
Adu
ltsA
dults
: bas
elin
e
Chi
ldre
nA
rm s
pan
Chi
ldre
n: y
early
Adu
ltsA
dults
: bas
elin
e
Chi
ldre
nW
eigh
tC
hild
ren:
yea
rly
Adu
ltsA
dults
: 18
year
s an
d ev
ery
5 ye
ars
Func
tion
Chi
ldre
nLo
wer
Lim
bFM
SC
hild
ren:
at d
iagn
osis
and
3, 6
, 8, 1
1, 1
5 ye
ars
end
of p
aedi
atric
car
e (<
18
year
s)C
linic
al
Chi
ldre
nPR
OM
IS P
edia
tric
Item
Ban
k v2
.0—
Mob
ility
—Sh
ort F
orm
8a
& PR
OM
IS P
aren
t Pro
xy It
em
Bank
v2.
0—M
obili
ty—
Shor
t For
m 8
a
Chi
ldre
n: a
t dia
gnos
is a
nd 6
, 8, 1
1, 1
5 ye
ars
end
of p
aedi
atric
car
e (<
18
year
s)Se
lf re
port
ed: f
rom
8 y
ears
and
old
erPa
rent
repo
rted
: all
ages
All
patie
nts
30 s
wal
k te
stC
hild
ren:
at d
iagn
osis
and
6, 8
, 11,
15
year
s en
d of
pae
diat
ric c
are
(< 1
8 ye
ars)
Adu
lts: 1
8 ye
ars
and
ever
y 5
year
s
Clin
ical
Adu
ltsPR
OM
IS It
em B
ank
v2.0
—Ph
ysic
al F
unct
ion—
Shor
t For
m 8
bA
dults
: 18
year
s an
d ev
ery
5 ye
ars
Self
repo
rted
Page 13 of 16Nijhuis et al. Orphanet J Rare Dis (2021) 16:140
Tabl
e 3
(con
tinue
d)
Patie
nt p
opul
atio
nM
easu
reM
easu
rem
ent t
ool
Tim
ing
(min
)D
ata
sour
ce
Chi
ldre
nU
pper
lim
b fu
nctio
nPR
OM
IS P
edia
tric
Item
Ban
k v2
.0—
Upp
er
Extr
emity
—Sh
ort F
orm
8a
& PR
OM
IS P
aren
t Pr
oxy
Item
Ban
k v2
.0—
Upp
er E
xtre
mity
—Sh
ort F
orm
8a
Chi
ldre
n: a
t dia
gnos
is a
nd 6
, 8, 1
1, 1
5 ye
ars
end
of p
aedi
atric
car
e (<
18
year
s)Se
lf re
port
ed: f
rom
8 y
ears
and
old
erPa
rent
repo
rted
: all
ages
Adu
ltsPR
OM
IS It
em B
ank
v2.0
—U
pper
Ext
rem
ity—
Shor
t For
m 7
aA
dults
: 18
year
s an
d ev
ery
5 ye
ars
Self
repo
rted
Chi
ldre
nSe
lfcar
ePR
OM
IS P
edia
tric
Item
Ban
k v2
.0—
Upp
er
Extr
emity
—Sh
ort F
orm
8a
& PR
OM
IS P
aren
t Pr
oxy
Item
Ban
k v2
.0—
Upp
er E
xtre
mity
—Sh
ort F
orm
8a
Chi
ldre
n: a
t dia
gnos
is a
nd 6
, 8, 1
1, 1
5 ye
ars
end
of p
aedi
atric
car
e (<
18
year
s)Se
lf re
port
ed: f
rom
8 y
ears
and
old
erPa
rent
repo
rted
: all
ages
Adu
ltsSU
NN
AA
S A
DL
Inde
x in
adu
ltsA
dults
: 18
year
s an
d ev
ery
5 ye
ars
Clin
ical
Qua
lity
of li
fe
Chi
ldre
nPa
inPR
OM
IS P
edia
tric
Item
Ban
k v2
.0—
Pain
Inte
r‑fe
renc
e—Sh
ort F
orm
8a
& PR
OM
IS P
aren
t Pr
oxy
Item
Ban
k v2
.0—
Pain
Inte
rfer
ence
—Sh
ort F
orm
8a
Chi
ldre
n: a
t dia
gnos
is a
nd 6
, 8, 1
1, 1
5 ye
ars
end
of p
aedi
atric
car
e (<
18
year
s)Se
lf re
port
ed: f
rom
8 y
ears
and
old
erPa
rent
repo
rted
: all
ages
Adu
ltsPR
OM
IS It
em B
ank
v1.0
—Pa
in In
terf
eren
ce—
Shor
t For
m 8
aA
dults
: 18
year
s an
d th
en e
very
5 y
ears
Self
repo
rted
Chi
ldre
nFa
ces
Pain
Rat
ing
Scal
e co
lore
d an
alog
ue
scal
eC
hild
ren
6, 8
, 11
year
sSe
lf re
port
ed
Adu
ltsPR
OM
IS It
em B
ank
v.1.
0—Pa
in In
tens
ity—
Scal
eA
dults
: 18
year
s an
d th
en e
very
5 y
ears
Self
repo
rted
Chi
ldre
nEm
otio
nal w
ellb
eing
PRO
MIS
Ped
iatr
ic It
em B
ank
v2.0
—A
nxie
ty—
Shor
t For
m 8
a &
PRO
MIS
Par
ent P
roxy
Item
Ba
nk v
2.0—
Anx
iety
—Sh
ort F
orm
8a
Chi
ldre
n: a
t dia
gnos
is a
nd 6
, 8, 1
1, 1
5 ye
ars
end
of p
aedi
atric
car
e (<
18
year
s)Se
lf re
port
ed: f
rom
8 y
ears
and
old
erPa
rent
repo
rted
: all
ages
Chi
ldre
nPR
OM
IS P
edia
tric
Item
Ban
k v2
.0—
Dep
res‑
sive
Sym
ptom
s—Sh
ort F
orm
8a
& PR
OM
IS
Pare
nt P
roxy
Item
Ban
k v2
.0—
Dep
ress
ive
Sym
ptom
s—Sh
ort F
orm
6a
Chi
ldre
n: a
t dia
gnos
is a
nd 6
, 8, 1
1, 1
5 ye
ars
end
of p
aedi
atric
car
e (<
18
year
s)Se
lf re
port
ed: f
rom
8 y
ears
and
old
erPa
rent
repo
rted
: all
ages
Adu
ltsPR
OM
IS It
em B
ank
v1.0
—Em
otio
nal D
is‑
tres
s—A
nxie
ty—
Shor
t For
m 8
aA
dults
: 18
year
s an
d th
en e
very
5 y
ears
Self
repo
rted
Adu
ltsPR
OM
IS It
em B
ank
v1.0
—Em
otio
nal D
is‑
tres
s—D
epre
ssio
n–Sh
ort F
orm
8a
Adu
lts: 1
8 ye
ars
and
then
eve
ry 5
yea
rsSe
lf re
port
ed
Chi
ldre
nFa
tigue
PRO
MIS
Ped
iatr
ic It
em B
ank
v2.0
—Fa
tigue
—Sh
ort F
orm
10a
& P
ROM
IS P
aren
t Pro
xy It
em
Bank
v2.
0—Fa
tigue
—Sh
ort F
orm
10a
Chi
ldre
n: a
t dia
gnos
is a
nd 6
, 8, 1
1, 1
5 ye
ars
end
of p
aedi
atric
car
e (<
18
year
s)Se
lf re
port
ed: f
rom
8 y
ears
and
old
erPa
rent
repo
rted
: all
ages
Adu
ltsPR
OM
IS It
em B
ank
v1.0
—Fa
tigue
—Sh
ort
Form
8a
18 y
ears
and
then
eve
ry 5
yea
rsSe
lf re
port
ed
Page 14 of 16Nijhuis et al. Orphanet J Rare Dis (2021) 16:140
Tabl
e 3
(con
tinue
d)
Patie
nt p
opul
atio
nM
easu
reM
easu
rem
ent t
ool
Tim
ing
(min
)D
ata
sour
ce
Chi
ldre
nSo
cial
func
tioni
ngPe
dsQ
L—Q
uest
ions
soc
ial f
unct
ioni
ng a
nd
scho
ol fu
nctio
ning
,C
hild
ren:
at d
iagn
osis
and
3, 6
, 8, 1
1, 1
5 ye
ars
end
of p
aedi
atric
car
e (<
18
year
s)Pa
tient
/par
ent r
epor
ted
Chi
ldre
nPR
OM
IS P
edia
tric
Item
Ban
k v2
.0—
Peer
Rel
a‑tio
nshi
ps &
PRO
MIS
Par
ent P
roxy
Item
Ban
k v.
2.0—
Peer
Rel
atio
nshi
ps
Chi
ldre
n: a
t dia
gnos
is a
nd 6
, 8, 1
1, 1
5 ye
ars
end
of p
aedi
atric
car
e (<
18
year
s)Se
lf re
port
ed: f
rom
8 y
ears
and
old
erPa
rent
repo
rted
: all
ages
Adu
ltsPR
OM
IS It
em B
ank
v2.0
—A
bilit
y to
Par
ticip
ate
in S
ocia
l Rol
es a
nd A
ctiv
ities
—Sh
ort F
orm
8a
Adu
lts: 1
8 ye
ars
and
then
eve
ry 5
yea
rsSe
lf re
port
ed
Adu
ltsPR
OM
IS v
2.0
Brie
f Pro
file
Sexu
al F
unct
ion
and
Satis
fact
ion
(Fem
ale)
Adu
lts: 1
8 ye
ars
and
then
eve
ry 5
yea
rsSe
lf re
port
ed
Adu
ltsPR
OM
IS v
2.0
Brie
f Pro
file
Sexu
al F
unct
ion
and
Satis
fact
ion
(Mal
e)A
dults
: 18
year
s an
d th
en e
very
5 y
ears
Self
repo
rted
Chi
ldre
nPa
rtic
ipat
ion
(edu
catio
n, w
ork,
le
isur
e an
d sp
orts
)Pe
dsQ
L—sc
hool
func
tion
(5 it
ems)
Chi
ldre
n: a
t dia
gnos
is a
nd 3
, 6, 8
, 11,
15
year
s en
d of
pae
diat
ric c
are
(< 1
8 ye
ars)
Patie
nt/p
aren
t rep
orte
d
Adu
ltsPR
OM
IS It
em B
ank
v2.0
—Sa
tisfa
ctio
n w
ith
Soci
al R
oles
and
Act
iviti
es—
Shor
t For
m 8
aA
dults
: 18
year
s an
d th
en e
very
5 y
ears
Self
repo
rted
Adu
ltsPR
OM
IS It
em B
ank
v2.0
—A
bilit
y to
Par
ticip
ate
in S
ocia
l Rol
es a
nd A
ctiv
ities
—Sh
ort F
orm
8a
Adu
lts: 1
8 ye
ars
and
then
eve
ry 5
yea
rsSe
lf re
port
ed
a Add
ition
al p
atie
nt/p
aren
t rep
orte
d tr
acki
ng p
ossi
ble
(“se
lf se
rvic
e”)
Page 15 of 16Nijhuis et al. Orphanet J Rare Dis (2021) 16:140
by the different countries and by both adults and child groups.
In order to structure the focus group meetings and their outcome, the items discussed were aggregated using the International Classification of Functioning, Disability and Health (ICF), a classification of health and health-related domains [13]. The items discussed were derived from a broad literature search. Since there was a wide range of outcome measures in the literature, efforts were made to create an overview of all reported outcomes. This was not a formal systematic literature review, how-ever all items were discussed and supplemented if nec-essary by the expert group. Certain domains were not retained as the expert group observed these outcomes generally remained stable over time. Therefore, meas-uring them would not reflect an outcome that could be influenced. For example, dental problems, height in adults and mortality. These items are reported only once in the baseline characteristics of each patient.
The lead team made a pre-selection of the measuring instruments. These measuring instruments were avail-able to the expert team for evaluation, in order to assess the face validity of the measuring instruments. It is pos-sible that either the lead team or the expert team over-looked some relevant measuring instruments. For certain domains the actual content may have been slightly bet-ter covered using different measuring instruments, but in order to keep the minimal standard outcome set man-ageable we preferred measures that cover several subdo-mains over multiple different measuring instruments per domain. The expert team consisted of patient representa-tives, clinical and scientific experts in the field of OI. It did not contain lawmakers, hospital administrators or insurance companies since we did not want to focus on what could be possible but on what is necessary to meas-ure in a minimal standard outcome set.
During this process of defining a standard outcome set for the care of people with OI, the guidelines for admin-istering the outcome set has not yet been addressed. In the next phase of this project, clinical care teams from different countries worldwide will pilot the standard out-come set. The frequency and feasibility of administering the measurements will be carefully assessed when used in routine clinical management as well as in research in OI. Guidelines as to how to implement this standard set in both settings will be formulated and published once the results of the experiences of the pilot teams are analyzed.
ConclusionThe international interdisciplinary Key4OI working group defined a standard set of recommended outcomes and associated measures that matter most to individuals with OI. This set of outcomes is recommended for use
by interdisciplinary teams caring for people with OI. It is only by agreeing on a standard set of outcome measures for the comprehensive assessment of OI that comparison of outcomes across centers, needed for quality-improve-ment endeavors, comparative effectiveness research, and value-based healthcare reform can become a reality in the future.
AcknowledgementsWe gratefully acknowledge Dagmar Mekking and the Care4Brittle Bones Foundation for initiating and supporting this project. The Key4OI is owned by Foundation Care4BrittleBones on behalf of everyone who contributed to its development. We gratefully acknowledge Pauline Scholten for her support in the literature search, creating a database accessible to the entire working group and preparing the content for the meetings.
Authors’ contributionsAll authors read and approved the final manuscript.
FundingMost work was done as a volunteer effort of all parties involved. Limited fund‑ing was provided by the Care4BrittleBones Foundation based on crowdfund‑ing in the OI‑community (no funding from industry).
Availability of data and materialsAll data generated or analyzed during this study are included in this published article. The datasets used and/or analyzed during the current study are avail‑able from the corresponding author on reasonable request.
Ethics approval and consent to participateFor some countries ethical approval was necessary; Belgium, The Netherlands, United Kingdom and The United States. In all of the other participating coun‑tries, a review was conducted and no ethical approval was required.
Consent for publicationNot applicable.
Competing interestsThe authors declare that they have no competing interests.
Author details1 University Medical Center Utrecht, Utrecht, The Netherlands. 2 Isala Zwolle, Utrecht, The Netherlands. 3 Cincinnati Children’s Hospital Medical Center, Cin‑cinnati, USA. 4 Shriners Hospitals for Children, Montreal, Canada. 5 University of Southern Denmark, Odense, Denmark. 6 University of Pavia, Pavia, Italy. 7 Riz‑zoli Institute Bologna, Milano, Italy. 8 Sheffields Children’s NHS Trust Founda‑tion, Sheffield, UK. 9 Nemours/Alfred Dupont Hospital for Children, Delaware, USA. 10 TRS National Resource Center for Rare Disorders, Sunnaas Rehabilita‑tion Hospital, Oslo, Norway. 11 ZOI (Flemish OI Association), Brussels, Belgium. 12 Advisor Care4BrittleBones Foundation, Montreal, Canada. 13 AS.IT.O.I. (Italian OI Association), Rome, Italy. 14 CHU de Toulouse, Toulouse, France. 15 Depart‑ment of Paediatrics, University of Cologne, Cologne, Germany. 16 China‑Dolls Center for Rare Disorders (CCRD), Bejing, China. 17 The University of Hong Kong ‑ Shenzhen Hospital, Hong Kong SAR, Shenzhen, China. 18 Children’s National Hospital, Washington, USA. 19 Shandong Provincial Hospital, Jihan, China. 20 Tartu University Hospital, Tartu, Estonia. 21 University Medical Center Erasmus Rotterdam, Rotterdam, The Netherlands.
Received: 3 July 2020 Accepted: 6 January 2021
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